The treatment of lung diseases by means of aerosols allows a targeted pharmaceutical therapy because the active agent can be delivered directly to the pharmacological target site by means of inhalation devices [D. Köhler and W. Fleischer: Theorie und Praxis der Inhalationstherapie, Arcis Verlag GmbH, München, 2000, ISBN 3-89075-140-7]. This requires that the inhaled droplets or particles reach the target tissue and are deposited there. The smaller the diameter of the aerosol particles, the greater is the probability that active agents reach the peripheral parts of the lungs. Depending on the kind and extent of the deposition, diseases such as asthma, chronic obstructive pulmonary disease (COPD) or pulmonary emphysema can be treated quasi-topically by inhalation. Moreover, systemically active agents such as insulin can be administered to the lung and taken up into the blood circulation by predominantly alveolar absorption. At present, mainly pressurized gas propelled metered dose inhalers, powder inhalers and nebulizers are used for the administration of active agents by inhalation. The type and extent of deposition at the target site depends on the droplet or particle size, the anatomy of the respiratory tract of humans or animals and on the breathing pattern. For the deposition of aerosols in the lungs of rodents such as rats, much smaller droplets are required than, for example, for horses, due to the smaller dimensions of the respiratory tract.
For pulmonary deposition in adults, aerosol droplets or particles should have an aerodynamic diameter of less than 5-6 μm, and for infants less than 2-3 μm. Moreover, infants breath through the nose, which is why nebulizing systems with a nasal mask should be used for the administration of active agents by inhalation. This restriction also applies in the case of other species such as rodents. The influences on the aerosol generation and deposition are mainly influenced by 3 factors which can be categorized as follows:    (1) bio-physiological factors, which are characterized by:            the kind of the breathing maneuver such as breathing frequency, flow, rate and volume,        the anatomy of the respiratory tract, in particular the glottal region,        the age and the state of health of the patient;            (2) the droplet or particle spectrum, which is, in turn, influenced by:            the kind and construction of the inhalation device,        the time interval between generation and inhalation (drying properties),        the modification of the droplet or particle spectrum by the respiratory flow,        the stability or integrity of the generated aerosol cloud;            (3) the active agent or active agent preparation, whose properties are influenced by:            the particle size,        the dosage form (for example, solution, suspension, emulsion, liposome dispersion),        the shape and surface properties of the active agent particles or the carrier particles (smooth spheres or folded porous structures) in the case of powder aerosols,        the hygroscopicity (influences the growth of the particles),        the interfacial properties such as wettability and spreadability,        the evaporation properties of the carrier medium.        
The advantages and disadvantages of the various inhalation devices and the possibilities to compensate inherent disadvantages have been discussed by M. Keller [Development and Trends in Pulmonary Drug Delivery, Chimica Oggi, Chemistry today, No. 11/12, 1998].
The question where aerosol particles are deposited in the bronchial tree has been the subject of numerous investigations for several years. These investigations are supplemented by constantly improving computational models of pulmonary deposition. The regional deposition pattern in breathing through the mouth shows a high degree of variability due to the breathing maneuver and the varying anatomy of the bronchial tree. The respirable size range of 0.5-6 μm, which is frequently mentioned in the literature, does not take into account the overlapping regions of deposition nor the quantitative or relative deposition rates.
In a healthy adult breathing through the mouth about 40-60% of the particles in the range of 2.5-4.5 μm are preferably deposited in the alveolar region. A bronchial deposition of the order of magnitude of about 5-28% is exhibited for particles of 2 to 8 μm, while the oropharyngeal deposition increases in parallel. For particles of 6 μm, the deposition in the oropharynx already amounts to 25-45% and increases to 60-80% for particles with a diameter of 10 μm. It follows from this that, for an optimal qualitative and quantitative alveolar deposition in adult, particle sizes of 1.5-3 μm are advantageous if the oropharyngeal and bronchial deposition is to be as low as possible. The bronchial deposition of about 18-28% for particles in the size range of 6-9 μm is relatively low and is always accompanied by a correspondingly higher oropharyngeal deposition. Depending on the state of health, the geometry of the bronchial system and the age of the patient, the orders of magnitude stated above shift to smaller particles sizes, in particular in children and babies. In the case of infants of less than 1 year of age, it is assumed that only droplets or particles with an aerodynamic diameter less than 2-3 μm reach the deeper regions of the lungs to a significant extent.
For the treatment of sinusitis it is also known that only the smallest aerosol droplets reach the sinuses through the small ostio openings such that more active agent can be deposited at the target site by means of a pulse aerosol than with continuous nebulization.
The deposition of aerosol particles in the respiratory act is essentially determined by the following four parameters:                the particle size,        the particle velocity,        the geometry of the respiratory tract, and        the inhalation technique or breathing maneuver.        
It can be derived from Stokes' law that the flow velocity and density of aerosol particles are relevant, which is why the aerodynamic and not the geometric particle diameter is used as the quantity to be measured for the deposition behavior in the respiratory tract. It is known from various investigations that only droplet or particle sizes with an aerodynamic diameter of about 0.6 μm-6 μm can be employed for pulmonary therapy. Particles with an aerodynamic diameter of greater than about 6 μm impact in the upper respiratory tract, whereas those which are smaller than about 1 μm are exhaled after inhalation. This implies that, for example, powders with very low density and an aerodynamic diameter of about 3 μm can have a geometric diameter of, for example, greater than 10 μm. In aqueous systems, on the contrary, with density of about 1 mg/cm3, the geometric and aerodynamic diameters are approximately equal.
The droplet compositions and form of aerosols are very diverse. Depending on the composition, aerosols may have a short or long life time; their droplet or particle size is subject to changes, which is influenced by the physical-chemical properties of the formulation components. Depending on atmospheric humidity, small aqueous droplets evaporate quickly to give a solid nucleus so that the concentration of the dissolved substance(es) upon complete evaporation is 100%. The resulting diameter (d2), starting from the original diameter (d1) corresponds to the cubic root of the concentration ratio before (c1) and after (c2) shrinkage (assuming a density of 1 g/cm3 for the dissolved substance) according to the formula: d2=d13√(c1/c2). Thus, for example, the drying of aerosols formed by coastal waves by the wind, in the case of a seawater droplet (c1=3.6%) of 20 μm, results in a salt particle with a diameter of about 6.7 μm, which has, thus, become respirable. This effect is employed, for example, in liquid nebulizers in order to reduce the particle size through drying effects (for example, heating by means of PARI Therm) or admixing of dry air.
On the contrary, in a humid environment, particles can grow and this growth is particularly dependent on the hygroscopicity of the active and/or auxiliary agent. For example, a dry sodium chloride particle of 0.5 μm requires about 1 second for complete growth, whereas in the case of a 5 μm particle this takes about 10 seconds, which proves that the velocity with respect to particle growth is also size dependent. Solid particles from powder nebulizers and metered dose inhalers can grow up to 4-5 times of their initial size since the humidity in the bronchial tree is 95-100%. (D. Köhler and W. Fleischer: Theorie und Praxis der Inhalationstherapie, Arcis Verlag GmbH, München 2000, ISBN 3-89075-140-7.)
For toxicological investigations, rodents and dogs are frequently used. Like infants, rodents breath through the nose, which is why in this case the aerosol should be applied by means of a nasal mask in order to achieve a high pulmonary deposition.
For the treatment of some pulmonary diseases such as asthma one mainly uses corticosteroids, beta-agonists and anticholinergic agents which are transported directly to the site of action by means of metered dose inhalers, powder inhalers and jet or ultrasonic nebulizers. The pulmonary application of corticosteroids for treatment of asthma has proven to be particularly advantageous compared to oral therapy because the underlying inflammatory process can effectively be inhibited with substantially lower active agent doses with marked reduction of adverse side effects. Active agents such as beclomethasone dipropionate (BDP), budesonide (Bud), and fluticasone propionate (FP) are mainly used as pump sprays for the treatment of allergic diseases in the nasal region, whereas metered dose inhalers (MDI), dry powder inhalers (DPI) and jet nebulizers are used for pulmonary application.
For the therapy of children under the age of 5 years powder inhalers are usually not suitable because children are not capable to generate flows of breath with which powders can reproducibly be de-agglomerated to give respirable particles and deposited in the lungs with sufficient dosage precision. Metered dose inhalers, on the other hand, have the disadvantage that the aerosol is released with a velocity of up to 100 km/h after operation of the valve. Due to insufficient coordination between the triggering of the spray pulse and inhalation, more than 90% of the active agent impact in the pharynx, which may result in unwanted side effect (hoarseness, voice changes, thrush, etc.). Moreover, the evaporation of the propellant gas can cause a cooling irritation, which, in hyper-reactive patients can result in a de-generation of the epiglottis or in an asthmatic attack, for which reason the inhalation of steroids should always take place with so called spacers with a volume of about 250-750 ml. For the application of steroids in infants, who cannot breath through the mouth, there are special types of spacers (for example Babyhaler®) for nasal breathing. However, the use of MDIs and spacers is very complex because active agents sediment, adsorb to the spacer walls or become electrically charged. This can result in insufficient dosage precision and in a non-reproducible pharmaceutical therapy. This is the reason why the nebulization of aqueous preparations by means of jet, membrane or ultrasonic nebulizers for the pulmonary application of active agents in children and infants is advantageous compared to metered dose inhalers and powder inhalers if sufficiently small droplets or particles are generated.
The ideal situation for a therapy by means of nebulization of an aqueous preparation is a pharmaceutical substance which is sufficiently soluble and stable in water or isotonic saline solution and whose physical-chemical characteristics do not change during manufacture and storage. If, however, the solubility of the pharmaceutical substance is too low to prepare and aqueous solution of sufficient concentration, nebulization in the form of a suspension may be considered. By means of a breathing simulator various nebulization efficiencies (deposited dose, fraction of the pharmaceutical substance remaining in the nebulizer, etc.) can be detected for the selected pharmaceutical form (suspension or solution). The respirable fraction of the generated aerosol can be determined by measuring the relative proportion of the active agent containing droplets having a geometric or aerodynamic diameter of less than 5 or 3 μm by means of laser diffraction or impactor measurement [N. Luangkhot et al.; Characterization of salbutamol solution compared to budesonide suspensions consisting of submicron and micrometer particles in the PARI LC STAR and a new PARI Electronic Nebuiser (eFlow™). Drug Delivery to the Lungs XI, 11 & 12 Dec. 2000, p. 14-17].
In the aforementioned investigation, it is reported that budesonide-containing suspensions in which the particle size of the suspended pharmaceutical substance is markedly smaller than 1 μm, unlike a microsuspension, can be nebulized with an efficiency similar to that of a salbutamol sulfate solution. This finding is confirmed by Keller et al. [Nebulizer Nanosuspensions. Important device and formulation interactions, Resp. Drug Delivery VIII, 2002, p. 197-206]. Moreover, it is pointed out that microsuspensions should not be nebulized with an ultrasonic nebulizer. In a case of the nebulization of a budesonide suspension (Pulmicort®) it could be shown by ultra centrifugation that about 4.6% of the budesonide in Pulmicort® are dissolved or solublized in molecularly dispersed form and that only this fraction can be aerosolized by an ultrasonic nebulizer.
The aqueous corticosteroid preparations which are currently commercially available are microsuspensions of beclomethason dipropionate (Clenil®), budesonide (Pulmicort®) and fluticasone propionate (Flixotide®) i.e., the micronized active agent (about 90% of the suspended pharmaceutical substance particles are smaller than 5 μm) is present in finely dispersed and stabilized form in water. The smaller the particle size is of the active agent and the smaller the density difference between active agent and dispersing medium, the longer the active agent remains in the suspension, i.e., the slower sedimentation usually takes place. Before the application, the sedimented particles or agglomerates must be redispersed in fine form by shaking of the packaging means in order to ensure that as small an amount as possible of the active agent remains in the container and the nebulizer can be filled with the nominal dose. For this purpose and for improved wetting of the lipophilic active agent surface with water a surfactant or wetting agent is added, which, however, must be inhalation-toxicologically safe in order to avoid unwanted side effects. As an example, Pulmicort® shall be referred to, which is commercially available in three concentrations 0.25, 0.5 mg and 1 mg of budesonide per 2 ml. Budesonide is suspended in saline solution which is buffered with citric acid and sodium citrate and contains polysorbate 80 (=Tween® 80) as a wetting agent. The mean particle size of 3 tested lots of Pulmicort® was greater than specified (about 2.8-3.2 μm) and scattered between 3.7 and 4.4 μm. This differing finding may possible due to the method of measurement (laser diffraction), but may also be due to particle growth or particle agglomeration. In a publication by Vaghi et al. [In-vitro comparison of Pumicort Respules with Clenil® per aerosol in combination with three nebulizers, ERS, Annual Congress Stockholm, Sep. 14-18, 2002], electron-microscopic pictures of Pulmicort® and Clenil® were shown from which it follows that the particles in Clenil® are needle-shaped and mainly greater than 10 μm, whereas the Pulmicort® particles are more rounded and have a diameter in the range of about 1-6 μm. A further disadvantage is that the aerosol characteristics of such microsuspension can change during nebulization. This can be derived, for example, from the increase of the budesonide concentration in the residual non-nebulized Pulmicort® suspension. The explanation for this effect is, inter alia, that greater particles cannot be transported by aerosol droplets which have a smaller diameter and, therefore, remain as residue in the nebulizer. In membrane nebulizers, the course particles are retained by the sieving effect of the membrane generating the aerosol. From an economical point of view, this is disadvantageous.
In-vitro investigations using a Baby Cast SAINT Model (Sophia Anatomical Infant Nose Throat) have shown that, upon use of Pulmicort® and a jet nebulizer, only about 1% of the nominal amount of active agent could be detected as the pulmonary dose. [Using Infant Deposition Models To Improve Inhaler System Design. Resp. Drug Delivery IX, 2004, p. 221-231]. These findings are partly in accordance with clinical findings by pediatricians who report an insufficient efficacy of the Pulmicort® nebulization therapy in infants and find the explanation for this in that not enough active agent can be transported into the lungs because both the par-ticles and the droplets are too big for infants.
Therapy of the nasal mucosa appears to be somewhat simpler to handle. Here it is usually possible even with simple devices for aerosol generation, such as mechanical atomizers to sprinkle the mucosa with an active agent containing preparation. However, in this case, too, poorly soluble active agents represent a challenge. The efficacy of active agent suspensions employed in practice is rather low and poorly reliable in comparison to the amount of active agent used, which is probably due to the particularly slow dissolution of the active agent in the small liquid volumes which are available on the nasal mucosa.
On the contrary, therapy of the mucosa in the poorly ventilated cavities of the upper respiratory tract is particularly difficult even with easily handled active agents, and all the more so with poorly soluble active agents. Usually, only a very small fraction of the dose of a suspended active agent in aerosolized form reaches the target tissue.